An emerging hybrid between the classical viral and non-viral gene delivery fields: synthetic virus-like vectors have gained ground. These condensed DNA particles carry one or more virus-like characteristics that make them more efficient at (a) certain step(s) of delivery, yet maintaining advantages over real viruses. The first goal of these studies is to lay the foundation for the construction of a novel family of such virus-like particles. We plan to use a variety of synthetic and traditional polymers and a variety of chemical approaches to form condensed and covalently cross-linked (caged) DNA particles with positive, negative and near-neutral surface potentials. Then the emphasis will be shifted to enhancing DNA nuclear transport, which is one of the most invincible obstacles to successful gene delivery. The efficiency of these particles in DNA nuclear delivery will be tested without or with covalently attached nuclear targeting signals, in microinjected cells. Based on the sub-cellular localization of labeled DNA and on the quantitation of marker gene expression (minimum 10-20x increase over control) the most efficient particle formulation technology(ies) will be selected. The particles then can be adjusted to the needs of many different delivery systems. PROPOSED COMMERCIAL APPLICATION: The nuclear transport technology developed in the proposed studies will be incorporated into gene therapy vectors with ligands for cellular receptors and with endosomolytic agents. Given that the non-viral vector industry realizes the power of inefficient nuclear transport to obstruct successful gene delivery, a new technology for overcoming this hurdle will have great commercial value.